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Monday, August 11, 2025

Hydantoin anticonvulsants


1. Definition and Overview

  • Hydantoin anticonvulsants are a class of antiepileptic drugs (AEDs) structurally derived from hydantoin, a five-membered heterocyclic ring containing two nitrogen atoms at positions 1 and 3 and a carbonyl group at positions 2 and 4.

  • First introduced in the 1930s, hydantoins remain important in the management of certain seizure disorders, particularly generalized tonic–clonic and partial seizures.

  • The most prominent and widely used agent is phenytoin, with others including fosphenytoin (a water-soluble prodrug of phenytoin) and mephenytoin (largely obsolete due to toxicity).

  • Their anticonvulsant effect is primarily due to stabilization of neuronal membranes and reduction of repetitive firing of action potentials by modulating sodium channel activity.

2. Chemical Features

  • Core structure: imidazolidine-2,4-dione (hydantoin nucleus).

  • Substitution at the 5-position with aromatic or alkyl groups is critical for anticonvulsant activity.

  • Modifications affect lipophilicity, protein binding, metabolism, and toxicity profile.

3. Mechanism of Action

  • Voltage-gated sodium channel modulation

    • Hydantoins bind preferentially to the inactive state of neuronal sodium channels.

    • Prolong the recovery from inactivation, thereby reducing the ability of neurons to fire at high frequencies.

    • Prevent spread of seizure activity without affecting normal neuronal excitability.

  • Additional minor actions:

    • Modulation of calcium channels.

    • Influence on potassium conductance.

    • Weak inhibition of glutamate release.

4. Pharmacokinetics

  • Absorption: Oral absorption variable; phenytoin exhibits slow, sometimes incomplete absorption.

  • Distribution: Highly protein bound (~90–95%), mainly to albumin. Hypoalbuminemia increases free drug fraction and toxicity risk.

  • Metabolism: Primarily hepatic via CYP2C9 and CYP2C19. Exhibits capacity-limited (zero-order) kinetics at therapeutic concentrations.

  • Excretion: Metabolites excreted renally.

  • Half-life: Variable (~22 hours for phenytoin), prolonged in overdose.

5. Therapeutic Agents

A. Phenytoin

  • Indications:

    • Generalized tonic–clonic seizures.

    • Partial seizures.

    • Status epilepticus (IV use; replaced by fosphenytoin in many settings).

    • Prevention of seizures after neurosurgery or traumatic brain injury.

  • Dosage forms: Oral capsules, chewable tablets, suspension, and IV injection.

  • Metabolism exhibits non-linear kinetics, requiring careful dose titration and monitoring.

B. Fosphenytoin

  • A prodrug of phenytoin with improved water solubility.

  • Administered IV or IM; rapidly converted to phenytoin in vivo.

  • Used mainly for status epilepticus and when oral administration is not possible.

C. Mephenytoin (obsolete in many countries)

  • Withdrawn or restricted due to severe idiosyncratic reactions including agranulocytosis and hepatitis.

6. Adverse Effects

Dose-related (toxic) effects:

  • Nystagmus, diplopia, ataxia, slurred speech, dizziness.

  • Cognitive slowing.

  • Sedation (less than with many other AEDs).

Chronic effects:

  • Gingival hyperplasia (overgrowth of gum tissue).

  • Hirsutism and coarsening of facial features.

  • Acne, skin thickening.

  • Peripheral neuropathy.

  • Folate deficiency and megaloblastic anemia.

  • Osteopenia/osteoporosis (via vitamin D metabolism interference).

Idiosyncratic effects:

  • Rash, Stevens–Johnson syndrome, toxic epidermal necrolysis.

  • Hepatotoxicity.

  • Hematologic reactions (leukopenia, agranulocytosis).

Fetal effects (teratogenicity):

  • Fetal hydantoin syndrome: craniofacial abnormalities, limb defects, growth retardation, neurodevelopmental delay.

7. Contraindications and Precautions

  • History of hypersensitivity to hydantoins.

  • Sinus bradycardia, SA block, second/third-degree AV block (for IV use).

  • Acute hepatic impairment (use with caution).

  • Pregnancy: teratogenic risk; use only if benefits outweigh risks, with folate supplementation.

  • Elderly and hypoalbuminemic patients require lower dosing.

8. Drug Interactions

  • Enzyme induction: Phenytoin is a potent inducer of CYP3A4, CYP2C, and UGT enzymes, reducing plasma concentrations of oral contraceptives, warfarin, cyclosporine, corticosteroids, some antiretrovirals, and other AEDs.

  • Enzyme inhibition/competition: Plasma levels increased by valproic acid, chloramphenicol, isoniazid, fluconazole, cimetidine, and others.

  • Protein binding displacement: Sulfonamides, valproic acid can increase free phenytoin levels.

  • Additive CNS depression with alcohol, sedatives.

9. Clinical Use Considerations

  • Narrow therapeutic index; target total plasma concentration usually 10–20 μg/mL.

  • Monitor serum levels regularly, especially after dose adjustments or with interacting drugs.

  • Adjust doses slowly due to non-linear kinetics.

  • Counsel patients on oral hygiene to reduce gingival hyperplasia.

  • Vitamin D and calcium supplementation may help prevent bone loss.

10. Advantages and Limitations

Advantages:

  • Effective in multiple seizure types (except absence seizures).

  • Less sedating than barbiturates.

  • Inexpensive and widely available.

Limitations:

  • Complex pharmacokinetics and potential for toxicity with small dose changes.

  • Multiple drug–drug interactions.

  • Chronic cosmetic and metabolic side effects.

  • Teratogenic risk.




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